Acta Anaesthesiol Scand 2014; 58: 1199–1213 Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12377

Review Article

A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain E. D. McNicol1, R. Schumann2 and S. Haroutounian3

1 Department of Anesthesiology and Pharmacy, Tufts Medical Center, Boston, MA, USA, 2Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA and 3Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA

While post-operative pain routinely resolves, persistent postsurgical pain (PPSP) is common in certain surgeries; it causes disability, lowers quality of life and has economic consequences. The objectives of this systematic review and meta-analysis were to evaluate the effectiveness of ketamine in reducing the prevalence and severity of PPSP and to assess safety associated with its use. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE through December 2012 for articles in any language. We included randomized, controlled trials in adults in which ketamine was administered perioperatively via any route. Seventeen studies, the majority of which administered ketamine intravenously, met all inclusion criteria. The overall risk of developing PPSP was not significantly reduced at any time point in the ketamine group vs. placebo, nor did comparisons of pain severity scores reach statistical significance. Sensitivity analysis of exclusively intravenous ketamine studies

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ost-operative pain routinely resolves after healing of the surgical site; however, in some patients, pain persists long after surgery. Persistent post-surgical pain (PPSP, also referred to as ‘chronic post-surgical pain’) is common, causes disability, lowers quality of life and has economic consequences.1 Reviews of its prevalence report that 22–67% of persons who underwent thoracotomy, 30–81% of persons who had a limb amputated, 11–51% of women who had breast surgery, 3–56% of persons who had a cholecystectomy and 0–37% of persons who had an inguinal hernia repair developed PPSP.1–4 Variations in estimates are in part due to differences in the definitions of PPSP. A common definition is that PPSP develops after a surgical procedure, is not from a pre-existing condition, is of at least 2 months duration, and that other causes of pain have been excluded.5 While this definition is comprehensive and was devel-

included in this meta-analysis demonstrated statistically significant reductions in risk of developing PPSP at 3 and 6 months (P = 0.01 and P = 0.04, respectively). Adverse event rates were similar between ketamine and placebo groups. The study data from our review are heterogeneous and demonstrate efficacy of intravenously administered ketamine only in comparison with placebo. Highly variable timing and dosing of ketamine in these studies suggest that no unifying effective regimen has emerged. Future research should focus on clinically relevant outcomes, should stratify patients with pre-existing pain and possible central sensitization and should enroll sufficiently large numbers to account for loss to follow-up in longterm studies. Accepted for publication 30 June 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

oped with the aim of accurately identifying PPSP, its applications in research are challenging, with some studies reporting its use, but not applying all criteria.6 Risk factors for developing PPSP include patient (demographic, psychosocial and genetic) and periprocedural or perioperative factors (duration and type of surgery, extent of intraoperative nerve damage, and intensity and duration of postoperative pain).1,7 Specific perioperative analgesic interventions may reduce the incidence of PPSP, but it is unclear which regimen is of most benefit. Evidence from the use of regional anesthesia and preemptive or multimodal analgesia has presented mixed results.1 While the development of PPSP is multifactorial, one of the major suggested mechanisms for the transition from acute to persistent post-operative pain is central sensitization.8 During surgery, repeated painful stimulation of primary afferent neurons

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results in the release of excitatory neurotransmitters, including glutamate, which binds to the N-methylD-aspartate (NMDA) receptor on the post-synaptic membrane in the dorsal horn. This event alters calcium influx into the second-order neuron, ultimately producing progressively increased depolarization of the post-synaptic membrane.9 Perioperative opioid administration may also contribute to hyperalgesia via similar mechanisms.10 The increased excitability and synaptic efficacy of neurons in central nociceptive pathways secondary to peripheral tissue damage and repeated nociceptive input is known as central sensitization; it reduces mechanical thresholds, exaggerates the response to noxious stimuli and facilitates a spread of sensitivity to normal tissue.8 Patients may report both hyperalgesia (increased sensitivity to painful stimuli) and allodynia (pain in response to normally nonpainful stimuli).9,11 Glutamatergic excitation occurs acutely and subacutely following peripheral injury to primary afferent neurons in animal models, and NMDA receptor blockade has been shown to attenuate spinal NMDA-mediated sensitization of dorsal horn neurons.12–16 Although the role of NMDA receptors in long-term central sensitization is unknown, the concept of perioperative NMDA receptor blockade to attenuate or prevent central sensitization and subsequent development of PPSP has generated increasing clinician interest. Ketamine, a noncompetitive NMDA receptor antagonist, may have a role in reducing the incidence of PPSP, when administered perioperatively.17 Ketamine is a general anesthetic when used in high doses. Even low (‘subanesthetic’) doses appear to reduce both pain and analgesic consumption in acute post-operative pain.18–20 Limited evidence also describes its effectiveness in both chronic noncancer and cancer pain populations.21,22 Ketamine may be administered intranasally, orally or subcutaneously, particularly when used for chronic pain, but is typically administered intravenously and occasionally epidurally in the perioperative setting. Patients may receive a bolus and/or continuous infusion, pre-, intra- and/or post-operatively. It may also be administered in combination with an opioid as a component of patient-controlled analgesia (intravenous or epidural) or with opioids and nonopioids in the context of a multimodal analgesic regimen. Analgesic doses employed clinically vary widely, but intravenous bolus doses in the range of 0.2– 0.75 mg/kg and infusions of 2–7 mcg/kg/min have been recommended.18,22,23 Common adverse reac-

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tions include cardiovascular (hypertension, tachycardia) and central nervous system (vivid dreams, visual hallucinations, emergence delirium) events, which are thought to be less common or severe at subanesthetic doses and with coadministration of a benzodiazepine.24 Ketamine is a chiral molecule and is typically administered as a racemic 50 : 50 mixture of the two enantiomers S-ketamine and R-ketamine. Both enantiomers bind to NMDA receptors, but S-ketamine is a more potent antagonist and a more powerful analgesic.25 The objectives of this systematic review and metaanalysis are to evaluate the effectiveness of ketamine administered perioperatively (pre-, intra- and postoperatively) in reducing the prevalence and severity of PPSP in adult patients and to assess both shortand long-term adverse events associated with its use in this setting.

Methods Inclusion and exclusion criteria We included randomized, placebo- or activecontrolled trials (RCTs), described as doubleblinded, in adults (aged 18 years and older) undergoing any type of surgical procedure involving incision and associated with PPSP. Recognizing that persistent pain maybe more easily prevented than reversed, we nonetheless included studies where patients may have had pre-existing pain, as we judged that stipulating patients who did not have pain pre-operatively would severely limit the number of eligible studies. We included studies administering any dose of ketamine by any route. Both single and multiple dose studies and studies employing continuous infusions were assessed. Studies where ketamine was administered in addition to a traditional analgesic (opioid and/or nonopioid) regimen in one study group and compared with a group receiving the same basic regimen (but without ketamine) were also included. For published studies, peer-reviewed journal publication was required; abstracts were not included unless they were less than 3 years old. We excluded studies with fewer than 10 participants to overcome random play of chance on estimation of treatment effect.26 We excluded studies of experimental pain, case reports and clinical observations.

Outcome measures Primary outcome: prevalence of PPSP. Our knowledge of the literature suggested that very few

Ketamine for prevention of PPSP

studies were rigorous enough to identify incidence and that assessment of prevalence varied between studies, particularly in regard to follow-up periods. We extracted incidence/prevalence of PPSP based on its definition within each study. Where data were presented in several formats, we chose the most liberal definition of PPSP in an effort to employ the most uniform possible outcomes reported across otherwise heterogeneous studies. For example, where a study reported ‘number of patients with pain intensity > 3’, ‘number of patients with pain worse than before surgery’ and ‘number of patients with any pain’ at a relevant time point, we chose the last definition as we expected this would be the most commonly reported. We meta-analyzed prevalence at 3 months, 6 months and 1 year or later. Secondary outcomes 1. Intensity or severity of PPSP as measured by either visual analog or verbal rating scales, respectively 2. Number of participants experiencing any serious adverse event 3. Number of participants experiencing specific adverse events 4. Severity of adverse events 5. Withdrawals due to adverse events We extracted adverse event data from the acute perioperative period and from subsequent longterm follow-up to the end point of each study.

Search methods for identification of studies We searched the following databases through December 2012: The Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and EMBASE (via Ovid). We combined search terms for ketamine, PPSP and randomized, controlled studies, without applying language restriction. The search strategy for MEDLINE was as follows: 1. exp Ketamine/ 2. (persist* or chronic).mp. or exp Postoperative Complications/ 3. 1 and 2 4. randomized controlled trial.pt. 5. controlled clinical trial.pt. 6. randomized.ab. 7. placebo.ab. 8. drug therapy.fs. 9. randomly.ab. 10. trial.ab. 11. groups.ab. 12. or/4–11

13. [animals not (humans and animals)].sh. 14. 12 not 13 15. 14 and 3 This strategy was adapted for each database. Additional studies were sought from the reference lists of retrieved articles and reviews. No attempt was made to assess reporting bias; however, we searched the clinical trial registry http:// www.clinicaltrials.gov in an attempt to minimize publication bias.

Data collection and analysis Data extraction was divided among the review authors, with each extraction being independently duplicated, using a standard form. Data suitable for pooling were entered into RevMan 5 software27 and double-checked by another author. Extracted data included information about the type of surgery and number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration and follow-up, outcome measures and results, withdrawals and adverse events.

Assessment of risk of bias in included studies Two review authors independently assessed the risk of bias of all included studies. The review authors made critical assessments for each of the following domains: sequence generation (randomization), allocation concealment, blinding, incomplete outcome data and selective outcome reporting. Review author judgment for each domain was entered into a risk of bias table, as either ‘low risk’, ‘high risk’ or ‘unclear risk’ (indicating either lack of information or uncertainty over the potential for bias).

Measures of treatment effect Discrete events such as the proportion of participants experiencing PPSP, or the proportion of participants reporting adverse events, were used to perform meta-analyses of risk ratio (RR) with 95% confidence intervals (CIs).28 When a statistically significant RR occurred between interventions, we also calculated the numbers needed to treat to benefit (NNTs) or harm (NNHs), which were derived from the absolute risk reduction (also known as risk difference). Meta-analyses were also undertaken when comparable data were available from continuous outcomes, such as severity of PPSP, using weighted mean differences. We used a fixed effect model for meta-analysis of both dichotomous and continuous outcomes. We performed sensitivity analysis to

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assess the robustness of our results by alternately undertaking meta-analysis using a random effects model. We performed a per-protocol rather than an intention-to-treat (ITT) analysis. In intervention trials for the treatment of existing conditions, participants lost to follow-up in an ITT approach are assumed to be nonresponders (i.e., still suffer from the condition). In this study, we assess the prevention of a potential event (PPSP) in patients receiving a brief perioperative intervention with ketamine. ITT analysis is not relevant in this case, as patients lost to follow-up cannot be assumed to experience or not to experience the event. Therefore, perprotocol analysis was used, and discrepancies between number of participants enrolled and number of participants in whom outcomes were reported are noted in Table 1.

Assessment of heterogeneity We visually assessed heterogeneity by studying forest plots and quantified statistical heterogeneity using the I2 statistic. An I2 value of greater than 50% is considered to indicate substantial heterogeneity.29 Where possible, we performed the following predetermined subgroup analyses in an attempt to explain heterogeneity: type of surgery, dosage regimen, route of administration, definition of PPSP and follow-up periods.

Results Results of the search Our literature search yielded 918 records (CENTRAL, 281; MEDLINE, 580; EMBASE 57). Our search of http://www.clinicaltrials.gov produced five studies (NCT 01017393, NCT00313378, NCT00726258, NCT01017393, NCT00354029), all of which were also published articles and were included in our literature search records.30–34 Fortythree articles were selected for full-text review (Fig. 1). Seventeen studies met all inclusion criteria.30–46 All included studies were published since 2000, with the majority being less than 5 years old, reflecting the relative novelty of using ketamine in this arena. All were placebo controlled. One study42 also included an active control group in which participants received gabapentin. In total, 1015 participants were randomized to receive ketamine and 785 to receive placebo, although a small percentage of participants withdrew from their respective studies before receiving their assigned intervention. The

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dose of ketamine administered varied both within and between studies. Some studies administered only a single bolus dose of ketamine, whereas the majority administered a bolus plus a subsequent continuous infusion. Boluses were typically administered immediately before surgery, with infusions started directly afterward and continued for up to 72 h post-surgically. The majority of studies administered ketamine intravenously (Suppa et al.43 administered an intramuscular bolus in addition to an intravenous infusion). Two studies employed the epidural route; both administered ketamine added to patient-controlled epidural analgesia.33,46 De Kock et al.36 included separate arms receiving either epidural or intravenous ketamine. Lastly, four studies that administered S-ketamine, either intravenously34,40,43 or epidurally,33 reported variously to be between two to four times as potent as the racemic mixture.47 Table 1 details the types of surgery performed and duration of follow-up.

Risk of bias in included studies All but three30,31,45 included studies described satisfactory methods of randomization; however, only nine studies adequately described methods of allocation concealment. Only 8 of the 17 studies used adequate methods to ensure blinding. In the other nine studies, the risk of bias was unclear because attempts at blinding participants, at blinding assessors or both were not adequately described. Two studies were assessed as being at high risk of attrition bias (incomplete reporting of outcome data).43,45 In both studies, there were a large number of participants in both arms lost to follow-up, with no description of the reasons for withdrawal. In the majority of studies, due to their long-term nature, there were considerable losses to follow-up, but these were generally balanced between arms along with similar reasons for withdrawal. For assessment of selective reporting, most studies reported on all of the outcomes described in their Methods sections and most of these we considered clinically relevant for this analysis. However, Sen et al.42 reported incidence of PPSP as being significantly lower in the gabapentin group but did not include supporting data, Suppa et al.43 evaluated residual pain at 6 months but did not report it and one study did not report adverse events.46 We were able to confirm that all outcomes were reported in the five studies also published on the trial registry http:// www.clinicaltrials.gov. Other potential sources of bias included the considerable variability in how each study defined PPSP, although we attempted to

Ketamine for prevention of PPSP Table 1 Summary of included studies, ketamine vs. placebo. Study

Surgery, time points when PPSP assessed, number of participants (enrolled/at each time point for selected ketamine regimen)

Ketamine regimen(s)

Definition of PPSP used in analysis

Secondary outcomes measured at 3 months or later

Results of secondary outcomes

Bilgen et al.35

C-Section under general anesthesia 6 months and 1 year. K: 35/35/35 P: 35/35/35 Radical mastectomy with axillary lymph node dissection 3 months K: 13/12 P: 18/18 Surgical resection of rectal adenocarcinoma 6 months and 1 year. K: 20/19/19 P: 20/18/17

B: 0.25, 0.5* or 1 mg/kg IV before induction of anesthesia

Any pain

Pain intensity (VRS): number of patients with mild, moderate, severe or no pain at all.

No participants had pain severity > mild at 6 months or 1 year.

B: 0.5 mg/kg IV before incision INF: 0.25 mg/kg/h infusion until end of surgery

NPSI and BPI used, but unclear how PPSP was defined

NPSI total score (0–100), % with hyperalgesia at wound site, surface area of site of hyperalgesia, nature of pain.

NPSI score very low in both groups (4.9 vs. 4.45). NS between groups for any secondary outcome.

B: 30 min before skin incision, INF: until end of surgery. IV arms: B 0.25 mg/kg, INF 0.125 mg/kg/h; or 0.5 mg/kg and 0.25 mg/kg/h* Epidural arms: B: 0.25 mg/kg, INF 0.125 mg/kg/h; or 0.5 mg/kg and 0.25 mg/kg/h. B: 1 mg/kg IV at induction INF: 1 mg/kg/h IV during surgery, then 1 mg/kg over 24 h B: 0.15 or 0.5 mg/kg* IV

‘Do you feel any pain at the scar area?’

Analgesic use in those reporting pain, pain at any other place, unpleasant manifestations experienced since operation.

Acetaminophen ± codeine sufficient in all participants experiencing residual pain. NS between groups for all other secondary outcomes.

NPSI > 0

NPSI total score, SF-36.

Participant rating of pain management as ‘excellent’, ‘acceptable’ or ‘poor’. For analysis, anyone reporting ‘acceptable’ or ‘poor’ assigned to prevalence of PPSP group. Patient-reported phantom or stump pain during previous 24 h (used stump pain for analysis)

Pain intensity (VAS 0–10) during rest and movement, patient satisfaction.

Median NPSI score = 0 in both groups. SF-36 scores did not differ between groups. No difference between groups, but orthopedic placebo subgroup had worst pain (P = 0.041).

Crousier et al.30

De Kock et al.36

Duale et al.31

Dullenkopf et al.37

Elective thoracotomy 4 months K: 42/34 P: 44/35 General and orthopedic (unspecified) 3 months K: 41/29 P: 33/25

Hayes et al.38

Above and below knee amputations 6 months K: 22/15 P: 23/17

B: 0.5 mg/kg pre-induction INF: 0.15 mg/kg/h × 72 h post-operatively

Joseph et al.32

Thoracotomy with partial pneumonectomy 3 months K: 24/18 P: 27/19

B: 0.5 mg/kg epidural at anesthesia induction INF: 3 mcg/kg/min epidural intraop, 1.5 mcg/kg/min × 48 h post-operatively

Limitation of daily activities

Katz et al.39

Radical prostatectomy 6 months K: 56/36 P: 50/38

Any pain at site of surgery

Mendola et al.40

Thoracotomy with partial or full pneumonectomy 3 and 6 months K: 33/31/29 P: 33/30/28

B: 0.2 mg/kg IV either 10 min before or 70 min* after incision INF: 2.5 mcg/kg/min IV for total of 80 min S (+) ketamine INF: 0.1 mg/kg/h IV via elastomeric pump, pre-incision × 60 h

Remerand et al.41

Total hip replacement 3 and 6 months K: 79/75/72 P: 75/72/70

B: 0.5 mg/kg IV pre-incision INF: 2 mcg/kg/min IV × 24 h

Unclear

Ryu et al.33

Thoracotomy 3 months K: 103/65 P: 106/68

Any pain around the incision site

Sen et al.42

Elective abdominal hysterectomy 3 and 6 months K: 20/20/20 P: 20/20/20 Hemorrhoidectomy K: 43/39 P: 39/38

S (+) ketamine PCEA (+ 0.12% levobupivacaine and 2 mcg/ml fentanyl). B: 1.2 mg as soon as patient arrived at operating room INF: 1.2 mg/h, additional boluses of 1 mg, lockout 20 min, until 3rd post-operative day B: 0.3 mg/kg IV 1 h before surgery INF: 0.05 mg/kg/h IV until end of surgery

‘Incidence of incisional pain’ – no further details. Not reported in Results

Pain intensity (VRS 0–10), impact of pain on daily activities.

S (+) ketamine B: 0.35 mg/kg IV immediately before incision INF: 5 mcg/kg/min until 2 min post-surgery

Any pain (NRS > 0) at rest

Pain intensity at rest, sitting and with defecation.

Spreng et al.34

NPSI > 1

Incidence of stump and phantom limb ‘troublesome pain’ (NRS ≥ 6), severity of stump and phantom limb pain (NRS highest, lowest or usual), duration of stump and phantom limb pain. Pain intensity (NRS 0–10) at rest and with movement, analgesic consumption, limitation of normal activity induced by pain, limitation of the abduction of the surgery side arm, any complication. MPQ, pain interference in daily life, methods of pain relief sought, medication use.

Worst pain intensity (NRS 0–10), pain localization, total amount of analgesics taken up to 6th post-operation month. PPSP considered mild for NRS 0–3, moderate and severe if hampering daily life. Pain intensity (NRS 0–100) at rest, with walking, in other locations, analgesic use, distance and difficulty walking. Pain severity (VAS 0–100) at rest and with movement, allodynia, numbness.

NS between groups for all secondary outcomes. Note: The development of significant phantom limb pain after day 3 was treated with amitriptyline and/or sodium valproate. NS between groups for all secondary outcomes.

NS in number of participants taking medication (none in any group). NS between groups for all other secondary outcomes. NS between groups for all secondary outcomes.

At 6 months, 10 P group vs. 3 K group NRS at rest > 3 (P = 0.04). NS between groups for all other secondary outcomes. NS between groups for all secondary outcomes.

Pain intensity low in both groups and NS different. Data not presented for impact on daily activities, but reported to be similar. NS between groups.

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E. D. McNicol et al. Table 1 Continued Study

Surgery, time points when PPSP assessed, number of participants (enrolled/at each time point for selected ketamine regimen)

Ketamine regimen(s)

Definition of PPSP used in analysis

Secondary outcomes measured at 3 months or later

Results of secondary outcomes

Suppa et al.43

Elective repeat C-section 3 years K: 28/13 P: 28/13

Any residual pain at the scar area

Thoracotomy, primarily for lung cancer 3 and 6 months K: 25/22/22 P: 25/22/22

Analgesic drugs used for wound pain, wound dysesthesia, pain in other sites, analgesic drugs for pain in other sites. Pain intensity (NRS 0–10) at baseline and worst, unpleasant sensations on the surgical wound, pt felt inconvenienced by the wound, number of pts who received pain medication.

All dichotomous, NS between groups.

Suzuki et al.44

S (+) ketamine B: 0.5 mg/kg IM 10 min post-partum INF: 2 mcg/kg/min IV × 12 h post-operatively INF: 0.05 mg/kg/h IV after intubation × 72 h post-operatively

Sveticic et al.45

Major elective orthopedic surgery 3 and 6 months K: 176/49/17 P: 176/42/19

Pain at the same location worse than before surgery

Pain intensity (VAS 0–10).

Wilson et al.46

Above and below knee amputation 3, 6 and 12 months K: 24/15/15/14 P: 29/19/16/15

PCA: 1.5 mg (+ 1.5 mg morphine) IV Q8 min prn up to 10× in 1 h, until pts required an average of < 1 PCA bolus/h during the last 12 h B: 0.5 mg/kg (+ 0.5% bupivacaine) epidural before starting surgery. INF: 3.3 mg/kg/l (+ bupivacaine 0.125%) epidural at 15 ml/h intraoperatively, 10–20 ml/h post-operatively × 48–72 h

Any pain in the stump

Pain intensity (VAS 0–10) of phantom and stump pain, MPQ, NPSI, QST, Hospital anxiety and depression scale, analgesic use.

Baseline (usual) NRS score of ≥ 1

Baseline pain intensity lower in K group at 3 months (P = 0.02). Number of pts who received pain medication lower at 3 months (P = 0.03). All other secondary outcomes NS between groups. Pain intensity NS between groups at 3 or 6 months.

Anxiety (P < 0.001) and depression (P = 0.003) reduced in K group vs. pre-operatively from 3 months until end of study, but not in P group vs. pre-operatively. All other secondary outcomes NS between groups.

*Regimen used in meta-analysis. K, Ketamine; P, placebo; B, bolus; INF, infusion; IV, intravenous; BPI, brief pain inventory; MPQ, McGill Pain Questionnaire; NPSI, neuropathic pain symptom inventory; NS, not statistically significant; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; QST, quantitative sensory testing; VAS, visual analog scale; VRS, verbal rating scale. PPSP, persistent post-surgical pain; NRS, numeric rating scale; IM, intramuscular.

homogenize data as much as possible, as described above. Also, the majority of studies were powered to show a difference in acute outcomes rather than for those measured at 3 months and later.

Primary outcome Sixteen studies presented data that contributed to the meta-analysis of prevalence of PPSP (Sen et al.42 did not report prevalence). In studies where more than one ketamine regimen was administered, we chose the dose closest to those used in other studies. We were able to perform sub-analysis at three separate time points: 3 months (for one study, we used data from 4 months31), 6 months and at 1 year or later. At 3 months, the overall RR of developing PPSP when both intravenous and epidural routes were assessed was 0.84 in the ketamine group vs. placebo; that is, a 16% relative reduction in the probability of developing PPSP, but this was not statistically significant (P = 0.06, 95% CI: 0.70–1.01) (Fig. 2). No single study demonstrated a statistically significant difference in PPSP risk between ketamine and placebo. Overall, 109 of 384 (28%) participants receiving ketamine reported PPSP at 3 months vs. 137 of 387 receiving placebo (35%).

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At 6 months and at 1 year or later, the overall RR was again not statistically significant when both intravenous and epidural routes were assessed. The overall number of participants reporting declined at each time point, with 260 participants from ketamine arms reporting at 6 months and 71 reporting at 1 year or later. For the 6-month and 1-year or later analyses only one study demonstrated a statistically significant reduction in risk of developing PPSP (at 6 months).41 In this study of patients undergoing hip replacement, 6 of 72 participants in the ketamine group vs. 15 of 70 participants in the placebo group reported PPSP (P = 0.04). One study compared ketamine with an active comparator, gabapentin.42 The authors reported that the prevalence of incisional pain was reduced in the gabapentin group at 3 and 6 months compared with both the ketamine and placebo groups, but did not present supporting data.

Secondary outcomes Mean intensity of PPSP was reported in five studies at 3 months and four studies at 6 months, using either a visual analog or verbal rating scale (zero indicating no pain, 10 indicating worst imaginable pain). At 3 months, the reduction in pain intensity in

Ketamine for prevention of PPSP 918 records identified through database searching

5 additional records identified through clinicaltrials.gov

568 records after duplicates removed

568 records screened

525 records excluded

26 full-text articles excluded:

43 full-text articles assessed for eligibility

No pain outcome at ≥ 3 months: n = 20 (many studies had additional reasons for exclusion) Ketamine part of multimodal strategy not employed in control arm: n = 1 All arms received same dose of ketamine: n = 1

17 studies included in qualitative analysis

Abstract > 3 years old: n = 1 < 10 participants in each group: n=1 Retrospective study: n = 1

17 studies included in quantitative synthesis (metaanalysis)

Single blind: n = 1

Fig. 1. Study flow diagram.

patients receiving ketamine (n = 154) vs. placebo (n = 147) was neither statistically nor clinically significant, applying interpretive standards for the latter described elsewhere.48 Results were similar at 6 months. There were insufficient data for metaanalysis beyond 6 months. No individual studies demonstrated a reduction in pain intensity at 3 months, and only one39 demonstrated a reduction in intensity in those receiving ketamine at 6 months. In this study, those receiving ketamine had a mean visual analog scale pain intensity of 2.8 ± 1.1 vs. those receiving placebo 3.4 ± 1.1 (P = 0.02), although the number of participants was low in each study arm (n = 36 and n = 38 in the ketamine and placebo groups, respectively). In the single active comparator study,42 participants in the gabapentin group reported lower pain

scores at 3 and 6 months vs. ketamine and placebo, although mean verbal rating scale scores were low in all groups. The authors stated that those receiving gabapentin suffered less impact of pain on their daily activities at 3 months, but did not present supporting data. Adverse events were almost exclusively monitored during the acute administration phase, either for the duration of the ketamine infusion or shortly thereafter. Adverse events were only mentioned at long-term follow-up (3 months and onward) in relation to participants withdrawing from the study.31,32,36,38,40,44,46 No long-term adverse events were attributed to the interventions by the investigators, and they appeared to be evenly balanced between ketamine and placebo groups. Mostly, long-term adverse events included death or recurrence of presenting disease, at rates typical in such populations. For adverse events monitored in the acute phase (typically up to 72 h post-operatively) and commonly associated with ketamine, there was no statistical difference between ketamine and placebo for hallucinations and nightmares/vivid dreams, but there was an increase in visual disturbances (e.g., nystagmus, diplopia), with an RR of 3.13 (95% CI: 1.65–5.94), translating to a NNH of around 9 (95% CI: 6–17). Similarly, there were no differences between ketamine and placebo for sedation, nausea and vomiting, which are adverse effects that might be expected to be less frequent in the ketamine arms because of reduced opioid consumption attributed to ketamine administration. The single study comparing ketamine with gabapentin reported no difference in the incidence of common side effects. There were insufficient data to compare study withdrawal rates because of adverse events or severity of adverse events. Lastly, there was no difference in the rate of serious adverse events, all of which were attributed to underlying disease and not to the interventions.

Subgroup analysis investigation of heterogeneity Dose of ketamine. We were unable to perform subgroup analysis based on dose of ketamine as the regimens varied widely, particularly in the dose and duration of continuous infusions. Follow-up period and surgical procedure. Results for each time point (3 months, 6 months and 1 year or later) and type of surgical procedure are presented as subgroups within our analyses of the primary outcome; however, participant numbers for individual procedures are small, and only arthroplasty

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Χ2

I2

P P

P

P

P

P

Χ2

I2

P P

Χ2

P P Χ2

I2 P

I2

Fig. 2. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: Incidence at 3 months, all studies. M-H, Mantel-Haenszel; CI, confidence interval.

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at 6 months shows a statistically significant reduction in PPSP in those participants receiving ketamine, with an RR of 0.43 (95% CI: 0.19–0.99). Route of administration. While subgroup analysis by route of administration was possible for the primary outcome, only three studies used the epidural route,33,36,46 therefore sub-analyses are presented for intravenous data only (including the study by Suppa et al.,43 which administered an intramuscular bolus before the intravenous infusion). Unlike the metaanalysis of combined routes, analysis of exclusively intravenous studies at 3 months demonstrated a statistically significant RR of 0.75 (P = 0.01, 95% CI: 0.60–0.93); that is, a 25% reduction in risk of developing PPSP. This translates to an NNT of 12; that is, on average, 12 patients would need to be treated with ketamine for one less patient to develop PPSP than would be the case if they received placebo (Fig. 3). Similarly, at 6 months, removal of epidural data resulted in meta-analysis demonstrating a statistically significant RR of 0.70 (P = 0.04, 95% CI: 0.50–0.98); that is, a 30% reduction in risk of developing PPSP (NNT of 14, Fig. 4). At 12 months or later, overall risk reduction remained nonstatistically significant for the intravenous data sub-analysis. Definition of PPSP. We scrutinized the prevalence of PPSP in the placebo group of each study. If each study was measuring the same outcome in similar populations and employing similar methodologies, PPSP rates should also be similar among studies of similar surgeries. In our analysis, where a study presented data that would allow more than one definition of PPSP prevalence (e.g., number of patients with pain intensity > 1 on 0–10 numeric rating scale), we chose the one which most closely aligned with other studies in an attempt to homogenize overall data (Table 1). Consequently, prevalence of PPSP in placebo groups in the included studies was generally consistent (and within ranges reported for various surgeries in the literature), but with some outliers. For example, placebo rates of PPSP in the included thoracotomy studies were 69%, 63%, 43% and 64% at 3 months, and 39% and 50% at 6 months. Removing studies with outlying rates did not significantly affect our analysis.

Sensitivity analysis We re-analyzed our results using random effects models. All meta-analyses that had previously not demonstrated a statistically significant difference

remained so. In addition, our sub-analyses of studies that only employed the intravenous or intramuscular route were no longer statistically significant; that is, at 3 and 6 months, although best point estimates were similar. For secondary outcomes, changing model of analysis had no effect on statistical significance of any of the analyses (i.e., they remained nonsignificant), with the exception of vision disorders, which, when analyzed using a random effects model no longer demonstrated statistical significance.

Discussion Summary of main results The results for our primary outcome demonstrate that perioperative ketamine reduces the risk of developing PPSP at 3 and 6 months, but only after removal of epidural studies from our metaanalyses. This result is consistent with a prior study. De Kock et al.36 compared epidural and intravenous routes and, perhaps surprisingly, given experimental work demonstrating the importance of spinal NMDA receptors in nociceptive input amplification, showed that intravenous, but not epidural, administration was successful in reducing analgesic requirements at 6 months after surgery. Several reasons may be considered for this apparently contradictory finding. The involvement of spinal NMDA receptors demonstrated in animal studies of peripheral nerve injury may be less important clinically in post-operative pain than previously thought.24 If spinal NMDA receptors do not serve as the primary target of ketamine, the lower plasma concentrations achieved with epidural administration when compared with intravenous administration49 likely translates to a lower systemic efficacy. On the other hand, ketamine given epidurally might be rapidly absorbed into the bloodstream via epidural veins, and the epidural ketamine dose might be lower than the IV doses employed, accounting for these results. Additionally, superior analgesia and opioidsparing effects associated with ketamine administration during the acute post-operative phase may be mediated primarily by attenuation of opioidinduced hyperalgesia, which has a substantial supraspinal component. Best point estimates at 6 months and at 1 year or later show a trend toward greater risk reductions in ketamine groups than at 3 months, suggesting that lack of statistical significance may be due to the small sample size at these later time points.

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Χ2

P P

I2

P

P

P

Χ2

P P

I2

Χ2

P P Χ2

I2 P

I2

Fig. 3. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: incidence at 3 months, intravenous studies only. M-H, Mantel-Haenszel; CI, confidence interval.

A 25% relative risk reduction in PPSP prevalence at 3 months in the intravenous meta-analysis is small, as reflected in the NNT of 12. Indeed, when sensitivity analysis was performed using a random effects model, the result was no longer statistically

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significant, reflecting the slim margin of statistical significance in our original analysis. However, even minor reductions in the incidence of PPSP may have a considerable public health impact. A 1996 estimate of cost savings based on preventing the transition

Ketamine for prevention of PPSP

Χ2

P P

I2

P

P

P

P

Χ2

P P

Χ2

P P Χ2

I2

I2 P

I2

Fig. 4. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: incidence at 6 months, intravenous studies only. M-H, Mantel-Haenszel; CI, confidence interval.

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from acute to PPSP in a 30-year-old patient, suggested that $1 million may be saved during the patient’s lifetime.50 At 3 months, both the Chi2 and I2 statistics imply that the data are homogeneous, apparently justifying the use of a fixed effect model; however, the variability in types of surgery, definitions of PPSP and dosing of ketamine suggest that heterogeneity does exist. The overall NNT of 12 may not be indicative of reductions in risk for specific surgeries where the prevalence of PPSP differs. In surgeries with a lower PPSP prevalence, reductions in risk of developing PPSP are likely to be of a lesser margin; that is, more patients would need to receive ketamine in order to achieve a statistically significant reduction in the incidence of PPSP, resulting in a higher NNT. The dosage regimens employed between studies were heterogeneous and prevented a subgroup analysis. However, in studies that assigned more than one ketamine regimen, higher doses of ketamine do not appear to consistently improve the persistent pain outcomes.35–37,39 Therefore, we cannot draw any conclusions regarding the optimal dose or timing (pre-emptive vs. preventative) of ketamine in reducing PPSP. It has been suggested that the inflammatory response may peak around 48 h post-surgery and therefore, ketamine should be administered for at least this duration postoperatively;33 but those studies32,34,38,40,44,46 that did administer ketamine for 48 h or longer did not demonstrate increased efficacy vs. those that did not. Similarly, the variability between studies in anesthetic and analgesic regimens employed in addition to ketamine precluded us from performing sensitivity analyses based on general vs. regional anesthesia or multimodal vs. conventional postoperative analgesia. Reductions in pain intensity in participants receiving ketamine were neither statistically nor clinically significant at either 3 or 6 months. However, the mean pain intensity was generally low at either time point in both ketamine and placebo groups. When subanesthetic doses of ketamine were administered, rates of ketamine-associated (including neuro-psychiatric) side effects did not differ between ketamine and placebo for the majority of comparisons, confirming a widely accepted clinical perception. The single statistically significant difference was observed for the rate of visual disturbances. However, the data were heterogeneous and may have reflected differences in definitions of, or methods of, reporting this adverse event. It appears

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that any reductions in opioid use in those treated with ketamine were not accompanied by reductions in opioid-induced side effects. Long-term safety data were scarce and what were available were not attributed to ketamine administration. Direct neurotoxicity of ketamine, particularly with intrathecal administration at high doses, has been reported in animal models.20,51,52 None of the included studies reported signs of clinical neurotoxicity, either acutely or in those patients completing long-term follow-up.

Overall completeness and applicability of evidence The included studies covered a wide variety of surgeries, but did not include many others associated with developing PPSP, such as nephrectomy, cholecystectomy or hernia repair. Additionally, adverse events were rarely monitored beyond the acute post-operative stage. The clinical relevance of the number of patients with ‘any pain’ at study endpoints is unclear, but the evidence would undoubtedly be more applicable if more of the studies had measured pain that was clinically meaningful to a patient. Lastly, it was unclear in many studies whether patients had pre-existing pain; that is, chronic pain before surgery. Therefore, the efficacy of ketamine in such a population has not been separately investigated.

Potential biases from the studies and the review process The 17 included studies generally had low or unclear risk of bias for the five assessed domains, with high risk occurring only in four studies and only for attrition and reporting bias. More likely, sources of bias included the low number of participants contributing data and the heterogeneity of reporting of PPSP. For the former, there were a mean number of 60 participants (median 42) assigned to receive ketamine in each study and a mean number of 46 (median 33) assigned to receive placebo, with the number of participants reporting data dropping substantially at later time points. As mentioned in the Methods section, we included studies where enrolled participants did have, or may have had, pre-existing pain of any kind. If we had included only those studies where the authors explicitly reported that they excluded patients with pre-existing pain, only five studies would have met the selection criteria.31–33,42,43 Our search strategies were concise and did not contain terms for individual surgeries; therefore, it

Ketamine for prevention of PPSP

is possible that we may have missed relevant studies. However, all included studies found in reference sections of other papers (original reports or reviews) were also found in at least one of our search strategies, suggesting that our searches were sufficiently sensitive. By searching for nonpublished data, we believe that our review is not subject to publication bias, but we did not contact study authors or manufacturers for unpublished studies.

Comparison with other reviews Several qualitative and quantitative reviews have studied the acute effects (7 days or less postoperatively) of perioperative ketamine. Findings were inconsistent both within and between reviews (based on different inclusion criteria for the latter) in the measured outcomes, which included pain intensity, opioid use and opioid-related and ketaminerelated adverse events.18,53–56 In general, any differences in the outcomes studied between ketamine- and placebo-treated patients were minor. One review of various agents for prevention of chronic pain after surgery employed different inclusion criteria to ours and did not perform an analysis of mean pain severity or of adverse events.57 Despite these differences, the review reported similar minor reductions in the number of patients developing chronic pain when comparing ketamine with placebo. As with our analysis, the above reviews discussed the heterogeneity of included studies and were unable to recommend an optimal timing or route of administration or dose regimen of ketamine. Direct extrapolations of short-term results to long-term effectiveness are challenging in that acute studies generally assess pain severity or opioid consumption, whereas long-term studies generally assess prevalence of pain as their primary outcome. However, many studies included in our review demonstrated short-term efficacy of ketamine that did not translate to long-term reductions in PPSP. This suggests that while increased acute pain appears to be a risk factor for developing PPSP,58 reduction of acute pain intensity may not be directly linked to reduced prevalence of developing persistent pain. Short-term studies may not predict longterm efficacy, but the reduced numbers of participants at later time points also impairs the ability to demonstrate a statistically significant result. In the future, larger studies presenting acute data for the subset of participants who also reported long-term data may clarify this relationship.

Conclusions In this meta-analysis of all eligible studies, combining intravenous and epidural administration, ketamine did not provide a significant reduction of PPSP at 3 and 6 months. In common with systematic reviews of short-term effects of ketamine on acute pain outcomes, the study data from our review of outcomes at 3 months or later are heterogeneous and suggest efficacy of intravenous ketamine only in comparison with placebo in preventing PPSP at 3 and 6 months. There was no evidence to support epidural ketamine administration for PPSP prevention. This may be important as concerns about direct ketamine neurotoxicity exist. Highly variable timing and dosing of ketamine in these studies suggest that no unifying effective regimen has emerged despite the long history of ketamine in clinical practice. Based on the variability of anesthetic and analgesic regimens employed, there may be increased efficacy of ketamine when used as part of a multimodal regimen. Given the multiplicity of neurotransmitters, growth factors and pathways involved in the transition from acute to chronic pain, it would seem logical that a combination of mechanisms should be targeted via a variety of approaches in order to increase the likelihood of inhibiting central sensitization. It is also unclear whether ketamine may be more effective in certain surgeries, or in specific populations, for example, in those who are opioid tolerant and/or who have pre-existing pain. However, these data suggest that perioperative ketamine is safe; therefore, it may be appropriate in patients undergoing painful surgeries or who are expected to require large doses of opioids postoperatively. We found insufficient data to make comparisons of ketamine with other interventions used to prevent PPSP. Future research should focus on clinically relevant outcomes; that is, pain that affects functioning or health-related quality of life. Several large studies recently addressed the risk factors for PPSP development,59,60 and future studies should attempt to stratify populations at high risk for PPSP, to identify which patients may benefit the most from specific interventions. It may be necessary to identify patients with pre-operative pain and possible central sensitization prior to enrollment. The dose and the duration of perioperative ketamine administration should be adequate to cover the critical period of susceptibility to central sensitization and neural plasticity. Lastly, sufficiently large numbers

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of patients should be enrolled to account for inevitable loss to follow-up in long-term studies. Conflicts of interest: No conflicts of interest declared. Funding: The review was funded in part by the Richard Saltonstall Charitable Foundation, USA. All other funding was departmental.

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Address: Ewan McNicol Departments of Anesthesiology and Pharmacy Tufts Medical Center 800 Washington Street, Box 420 Boston, MA 02111 USA e-mail: [email protected]

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